title: Selective cannabinoid receptor type 2 (CB2) agonists: optimization of a series of purines leading to the identification of a clinical candidate for the treatment of osteoarthritic pain.
abstract: A focused screening strategy identified thienopyrimidine 12 as a cannabinoid receptor type 2 agonist (hCB2) with moderate selectivity over the hCB1 receptor. This initial hit suffered from poor in vitro metabolic stability and high in vivo clearance. Structure-activity relationships describe the optimization and modification to a new more polar series of purine CB2 agonists. Examples from this novel scaffold were found to be highly potent and fully efficacious agonists of the human CB2 receptor with excellent selectivity against CB1, often having no CB1 agonist activity at the highest concentration measured (>100 μM). Compound 26 is a centrally penetrant molecule which possesses good biopharmaceutical properties, is highly water-soluble, and demonstrates robust oral activity in rodent models of joint pain. In addition, the peripherally restricted molecule 22 also demonstrated significant efficacy in the same analgesic model of rodent inflammatory pain.
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly and Company , Lilly Corporate Center, Indianapolis, Indiana 46285, United States.
authors.forename: Sean P
authors.initials: SP
authors.lastname: Hollinshead
authors.forename: Michael W
authors.initials: MW
authors.lastname: Tidwell
authors.forename: John
authors.initials: J
authors.lastname: Palmer
authors.forename: Rossella
authors.initials: R
authors.lastname: Guidetti
authors.forename: Adam
authors.initials: A
authors.lastname: Sanderson
authors.forename: Michael P
authors.initials: MP
authors.lastname: Johnson
authors.forename: Mark G
authors.initials: MG
authors.lastname: Chambers
authors.forename: Jennifer
authors.initials: J
authors.lastname: Oskins
authors.forename: Robert
authors.initials: R
authors.lastname: Stratford
authors.forename: Peter C
authors.initials: PC
authors.lastname: Astles
mesh_terms: D000818:Animals; D004285:Dogs; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D010003:Osteoarthritis / Q000188:drug therapy*; D011687:Purines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000627:therapeutic use; D051381:Rats; D011917:Rats, Inbred Lew; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: D011687:Purines; D043885:Receptor, Cannabinoid, CB2; D016244:Guanosine 5'-O-(3-Thiotriphosphate)